Nanoemulsions for Diagnostics and Therapy

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Nanoemulsions (NEs) are colloidally disperse systems. Similar to liposomes, their particular sizes measure up to several hundreds of nanometers (for explanation, a nanometer is a millionth of a millimeter).

Just like in liposomes, the interfacial surface of NEs may consist of phospholipids. For this reason, the bodily distribution of such NEs - i.e., when employed as drug carriers - is similar to the biodistribution of liposomes. In parenteral applications, the external medium consists of a hydrophilic phase.

NEs for Specific Drug Targeting

Lipophilic active ingredients can be incorporated into the oil phase present within the interior space of conventional nanoemulsions. Due to the fact that nanoemulsions have a larger lipophilic phase than liposomes, they can absorb higher amounts of oil-soluble active ingredients.

Such nanoemulsions (a.k.a. "sub-micron emulsions") are mainly used in the field of parenteral fat diet. However, there are also drug-containing products in the market place; these comprise for example NEs that contain anesthetics.

At this Department, we investigate different aspects of nanoemulsions. For example, as part of her PhD thesis Dr. Wan-Hsun Wu examined options for employing NEs that contain cytostatic (anti-cancer) drugs in the form of infusions, or for injection (in collaboration with Professor Dr. Heinz-Herbert Fiebig, Oncotest GmbH, Freiburg, Germany).

These works will be continued in the PhD thesis by Ms. Shila Gurung. Nanoemulsions are predominantly produced by high-pressure homogenization on a larger scale. This requires a high amount of material and, in addition to the nanoemulsion droplets, larger amounts of liposomes are present as well. This dissertation thus focuses on (i) minimizing the liposome content, (ii) examining methods for manufacturing such emulsions at small scale, and (iii) finding suitable surface modifications to actively address target cells either by coupling of antibodies or via other ligands.

Among other objectives, the PhD thesis of Dr. Hendrik Hardung focused on the delivery of active pharmaceutical agents into the skin after topical application of NEs, as well as on their interaction with cells of the skin.

Fluorine-loaded Nanoemulsions for Diagnostic Purposes: In-vivo Monitoring of Inflammatory Processes via ¹H/¹⁹F MRI

So far, the MRI-dependent detection of local inflammatory processes has only been feasible upon employing super paramagnetic iron oxide particles (SPIOs). Particularly convenient is the high affinity of these particles to the monocyte-macrophage system (MPS). SPIOs lead to extinction of the MR signal. Thus, according to local enrichment merely a slowdown in the MR image is to recognize what sometimes makes it difficult to interpret the data.

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In collaboration with the Institute for Heart and Circulation Physiology, University of Düsseldorf, Germany (Professor Dr. Jürgen Schrader, Dr. Ulrich Flögel), we are planning to establish a positive-contrast MRI methodology for demonstrating inflammatory processes.

Here, we employ the physically, chemically and physiologically inert perfluorocarbons (PFCs) as contrast agents. Using biocompatible excipients, such PFCs are processed into nanoemulsions, which - similar to the SPIOs - are phagocytized in vivo by monocytes/macrophages.

Using various models of acute inflammation - such as for cardiac or cerebral infarction - the nanoemulsion was evaluated in mice. After intravenous administration, the nanoemulsion was ingested by mononuclear phagocytes where upon it accumulated in inflammatory infarction areas in which the NE could be detected in vivo by MRI. According to experience, the uptake of nanoscaled particles by mononuclear phagocytes depends on their size. Our research thus comprised the production of different defined sizes of nanoemulsions as well as studies on the cellular uptake of these defined particles in vitro.

PFCs can thus be employed as positive radiopaque agents for depicting inflammatory processes. Due to the lack of a natural ¹⁹F background in vivo, they have a high degree of specificity as contrast agents. Moreover, the procedure should be suitable for application in humans (i) because PFCs are nontoxic, and (ii) since various perfluorinated compounds such as Perflubron® have already been sufficiently studied as to their toxicological properties when employed as blood substitutes (e.g., including their elimination) (PhD theses by Dr. Hendrik Hardung and Dr. Friederike Mayenfels).

Fluorine-loaded Nanoemulsions for Diagnostic Purposes: Active Targeting via Perfluorocarbon-loaded Nanoemulsions (PFC-NEs)

Active targeting of nanoparticles to defined target structures gains increasing importance in both research and for therapeutical applications. The use of perfluorocarbon nanoemulsions that specifically bind to target structures on pathologically altered cells promise to enable detecting states of disease both at earlier points in time as well as much more precisely than currently feasible.
Active targeting via PFC-NEs has therefore been broadly investigated in in vitro. Based on these results, we are currently in the process of setting up in vivo experiments in mice (PhD thesis by Christoph Grapentin).

Funding
Research on perfluorocarbon nanoemulsions has been funded by the German Research Foundation (DFG) since 2010.